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Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon.
Stem Cells. 2017 03; 35(3):705-710.SC

Abstract

The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and coexpress markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult preinjury restricted cells coexpressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl), tendons and joints formed HO. Postnatal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive BMP receptor (e.g., caACVR1) activity. Stem Cells 2017;35:705-710.

Authors+Show Affiliations

Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Sports Medicine, Tenri University, Japan.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Michigan, USA.Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.Department of Orthopaedic Surgery, Orthopaedic Research Laboratories, University of Michigan, Michigan, USA.Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27862618

Citation

Agarwal, Shailesh, et al. "Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon." Stem Cells (Dayton, Ohio), vol. 35, no. 3, 2017, pp. 705-710.
Agarwal S, Loder SJ, Cholok D, et al. Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon. Stem Cells. 2017;35(3):705-710.
Agarwal, S., Loder, S. J., Cholok, D., Peterson, J., Li, J., Breuler, C., Cameron Brownley, R., Hsin Sung, H., Chung, M. T., Kamiya, N., Li, S., Zhao, B., Kaartinen, V., Davis, T. A., Qureshi, A. T., Schipani, E., Mishina, Y., & Levi, B. (2017). Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon. Stem Cells (Dayton, Ohio), 35(3), 705-710. https://doi.org/10.1002/stem.2515
Agarwal S, et al. Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon. Stem Cells. 2017;35(3):705-710. PubMed PMID: 27862618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon. AU - Agarwal,Shailesh, AU - Loder,Shawn J, AU - Cholok,David, AU - Peterson,Joshua, AU - Li,John, AU - Breuler,Christopher, AU - Cameron Brownley,R, AU - Hsin Sung,Hsiao, AU - Chung,Michael T, AU - Kamiya,Nobuhiro, AU - Li,Shuli, AU - Zhao,Bin, AU - Kaartinen,Vesa, AU - Davis,Thomas A, AU - Qureshi,Ammar T, AU - Schipani,Ernestina, AU - Mishina,Yuji, AU - Levi,Benjamin, Y1 - 2016/11/08/ PY - 2016/07/10/received PY - 2016/09/16/accepted PY - 2016/11/20/pubmed PY - 2017/12/20/medline PY - 2016/11/19/entrez KW - Adult stem cells KW - Bone KW - Fibrodysplasia ossificans progressiva KW - Heterotopic ossification KW - Osteoblast KW - Progenitor cells KW - Skeleton KW - Tissue specific stem cells SP - 705 EP - 710 JF - Stem cells (Dayton, Ohio) JO - Stem Cells VL - 35 IS - 3 N2 - The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and coexpress markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult preinjury restricted cells coexpressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl), tendons and joints formed HO. Postnatal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive BMP receptor (e.g., caACVR1) activity. Stem Cells 2017;35:705-710. SN - 1549-4918 UR - https://www.unboundmedicine.com/medline/citation/27862618/Scleraxis_Lineage_Cells_Contribute_to_Ectopic_Bone_Formation_in_Muscle_and_Tendon_ L2 - https://doi.org/10.1002/stem.2515 DB - PRIME DP - Unbound Medicine ER -